Exosomes as emerging mediators and therapeutic vehicles in painful diabetic neuropathy: From pathophysiology to clinical translation

Table 6 Summary risk-of-bias assessment for key preclinical studies contributing to Table 5 efficacy ranges (Systematic Review Centre for Laboratory animal Experimentation tool) and the human randomized controlled trial (Cochrane Risk of Bias 2.0)

Ref.	Study type	Model/population	Sequence generation	Baseline characteristics/allocation concealment	Random housing/blinding of personnel	Blinded outcome assessment	Incomplete outcome data	Selective outcome reporting	Overall RoB
Fan et al[13], 2020	Preclinical (SYRCLE)	STZ-induced diabetic mouse; MSC-derived exosomes; IV administration	Unclear	Unclear	Unclear	High (behavioral endpoints unblinded)	Low	Unclear	High
Shan et al[12], 2022	Preclinical (SYRCLE)	STZ-induced diabetic mouse; SIRT1-enriched bone marrow MSC exosomes	Unclear	Unclear	Unclear	High (unblinded outcome assessment reported)	Low	Unclear	High
Jia et al[23], 2018	Preclinical (SYRCLE)	STZ-induced diabetic rat; high glucose-conditioned Schwann cell exosomes	Unclear	Unclear	Unclear	High (behavioral endpoints)	Low	Low	High
Lu et al[24], 2025	Systematic review/meta-analysis (SYRCLE applied to included studies)	STZ-induced diabetic rodents; cell-derived exosomes	Unclear (majority of included studies)	Unclear (majority)	Unclear (majority)	High (majority of included studies)	Low	Low	High (majority of included studies)
Karkhaneh Yousefi et al[25], 2025	Human RCT (Cochrane RoB 2.0)	Diabetic foot ulcer patients; Wharton’s jelly MSC-derived exosomes	Low	Low	Some concerns (personnel not blinded to treatment)	Some concerns (outcome assessors partially blinded)	Low	Low	Some concerns

STZ: Streptozotocin; IV: Intravenous; MSC: Mesenchymal stem cell; RCT: Randomized controlled trial; SYRCLE: Systematic Review Centre for Laboratory animal Experimentation; RoB: Risk of Bias.